The Cancer Stem Cell model of carcinogenesis has recently garnered a great deal of attention. Cancer stem cells have been identified in acute myelogenous leukemia, as well as in solid malignancies such as those of the breast, colon and brain. Although there exists evidence of a tumor-initiating population in multiple myeloma (MM), to date the markers positively identifying such cells are unknown. The hierarchical organization of the hematopoietic system and the observation that a majority of MM cells are unable to form tumors at high frequency support a role for stem cells in the maintenance and progression of the disease. Given that MM is the second most common blood cancer in the United States and relapse occurs in 100% of patients, the potential role of cancer stem cells in MM warrants attention. The power in visualizing cancer stem cells stems from the identification of cellular markers that distinguish the rare tumor-initiating cells from the bulk of malignant cells. Although there is some data suggesting that cells negative for CD138 expression are the MM cancer stem cells, identification based on the lack of antigen expression is not ideal for therapeutic targeting, diagnostic, or in vivo imaging purposes. We have proposed to screen for antibodies that identify MM cancer stem cells by positive selection with phage display technology which allows for the screening of 1010 antibody clones. Prior to the screening of phage we will first enrich for putative cancer stem cells based on side population analysis (or lack of CD138 cell surface expression). Positive markers will be validated under in vivo conditions with MM cell lines as well as MM patient specimens. The identification of cancer stem cell markers is likely to advance disease prognostication and alter standard therapeutic strategy by promoting the development of cancer stem cell targeting therapeutics to be used in conjunction with standard chemotherapy. In the event that the cancer stem cell model is validated, the prevention of relapse and the potential for a cure of MM patients will be within reach.